: Cognitive impairment is a common complication of HIV- 1 infection that can lead to dementia. The use of potent anti-retroviral therapy has dramatically improved survival and decreased the incidence of systemic HIV complications, including neurological complications. However, the increased survival is likely responsible for the unchanged prevalence of neurological disorders shown recently in longitudinal studies (NEAD cohort). The implication of these findings are that although controlling HIV-1 replication remains the most important goal in the treatment of HIV infection and its neurological sequelae, pathological mechanisms indirectly linked to HIV infection may persist despite optimal viral suppression. This may explain why the presence of macrophage activation in the brain correlates best with dementia. This suggests that the best approach to treat cognitive impairment should consist of best anti-retroviral therapy and adjunctive therapy aimed at indirect mechanisms of neuronal injury. In the background of a systemic disease such as HIV infection treated with multiple drugs that have complex interactions, there are two important steps in the development of novel compounds for the treatment of cognitive impairment. The first step is to assess the pharmacokinetic interaction of a study drug with antiretrovirals (Phase Ia). The second step is to assess the safety and tolerability profile of a study drug in the HIV infected population (Phase Ib) rather than the normal HIV negative population. In such Phase I trials, in vivo brain metabolism (magnetic resonance spectroscopy) may be an important adjunctive tool to detect early cerebral changes that may not be evident clinically. We propose to establish a Phase I Clinical Trials Unit to perform hypothesis driven clinical trials of agents shown by our in vitro and in vivo models to favorably act on mechanisms thought to be critical in the pathogenesis of HIV dementia. The specific aims of this Clinical Trials Unit are: 1. to conduct a series (yearly) of Phase Ia pharmacokinetic interaction studies in HIV infected individuals; 2. to conduct a series (yearly) of Phase Ib clinical trials in HIV infected patients at risk for HIV dementia to ascertain safety and tolerability, and to assess the impact on cognitive performance and brain metabolism of novel therapeutic agents; 3. to operate a Clinical Trials Coordination Center to support and promote the rapid and efficient conduct of the Phase I trials. An infrastructure for conducting Phase II and III trials is already in place and would therefore fast track the transition from Phase I to later stages of drug development.